Numerous population and animal studies have established the atheroprotective properties of high density lipoproteins (HDL). In addition to its main antiatherogenic property of extracting cholesterol from peripheral cells and transferring it to the liver for excretion (reverse cholesterol transport, RCT), HDL also possesses anti-inflammatory and antioxidant properties. An emerging area in the field of HDL therapy is the development of apolipoprotein mimetic peptides. We have shown that orally administered apoA-l-mimetic peptides result in a dramatic reduction in the atherosclerotic lesion formation in atherosclerosis-sensitive mouse models despite no change in cholesterol levels. We hypothesize that this occurs via the formation of preB-HDL-like particles that possess increased paroxonase-1 (PON1) activity which are able to destroy lipid hydroperoxides (LOOH) and enhance reverse cholesterol transport, the major antiatherogenic properties of apoA-l. Thus antiatherogenic peptides modulate the properties of HDL such that proatherogenic HDL is converted into antiatherogenic HDL. We propose two mechanisms for the formation of both antiatherogenic a and preBHDL in the presence of antiatherogenic peptides: 1) enhanced interaction with ABCA1 to form increased levels of apo A-l-only containing particle with increased amounts of PON1 levels of preB-HDL particles; and 2) enhanced receptor (SRB-1) interaction of a-HDL particles to clear cholesteryl ester, thus regenerating active preB-HDL particles. We hypothesize that the antiatherogenic properties are governed by the ability of the peptide (peptide-lipid complexes) to recruit apoA-l, LOOH, and enzymes such as PON1 present in HDL. If, for example, PON1 is not active on these particles, this HDL is inflammatory since it possesses LOOH. To test our hypothesis we propose the following specific aims: 1a. Influence of peptide structure on the composition of HDL. 1b. Structural aspects of peptide association; 2a. Antiatherogenic potential of each peptide. 2b. Testing of selected peptides for their antiatherogenic properties in atherosclerosis sensitive mouse models. We will use physical, physico-chemical, in vitro cell culture and in vivo studies in animal models of atherosclerosis to characterize the structure and function of peptidemediated HDL changes that are related to antiatherogenic properties. These studies will for the first time enable us to understand the detailed structural aspects of peptide-modulated antiatherogenic HDL and the mechanism of antiatherogenic and anti-inflammatory actions of apoA-l-mimetic peptides. Furthermore, these studies will lead to the design of simple molecules with increased antiatherogenic and anti-inflammatory potencies and potentially lead to novel modalities to ameliorate atherosclerosis.